Causal inference analysis of the effect of amyloid-β and tau proteins on dementia risk: A Mendelian randomization analysis

Background The global burden of dementia is escalating due to the aging population. While amyloid and tau biomarkers are central to Alzheimer's disease (AD) pathology, their causal roles across dementia subtypes are not fully understood. Objective This study investigated the causal effects of cerebrospinal fluid (CSF) and plasma amyloid, tau, and hyperphosphorylated tau (p-tau) proteins on dementia [AD, frontotemporal dementia (FTD), and vascular dementia (VaD)] risk. Methods In this study, we conducted a two-sample Mendelian randomization analysis using genome-wide association study (GWAS) summary statistics. The AD, CSF, and plasma amyloid, tau, and p-tau data were obtained from the GWAS catalog, while those for FTD and VaD were obtained from the FINNGEN database. The inverse variance weighting method, combined with sensitivity analysis, was used to obtain the estimates. Results CSF p-tau in individuals with abnormal amyloid and APOE ε4 non-carriers was positively associated with AD risk [IVW: OR = 1.07, 95% CI = 1.01–1.13, p = 0.016; OR = 1.08, 95% CI = 1.02–1.14, p = 0.014, respectively]. CSF p-tau was also associated with VaD (IVW: OR = 1.11, 95% CI = 1.03–1.20, p = 0.008). Plasma Aβ 1−42 reduced the odds of FTD (IVW: OR = 0.83, 95% CI = 0.70–0.98, p = 0.03), whereas CSF Aβ 42 increased FTD risk (weighted median: OR = 1.58, 95% CI = 1.02–2.44, p = 0.041). Conclusions The findings support the causal roles of tau and amyloid across dementia subtypes, reinforcing the value of biomarker-driven prevention and therapeutic strategies.